AusPAR Antizol Fomepizole AFT Pharmaceuticals PM-2015-02803-1-3 Final 17 August 2017 PRODUCT INFORMATION NAME OF THE MEDICINE ANTIZOL® fomepizole injection -1 C4H6N2 82.1 g mol Fomepizole (4-methylpyrazole) CAS registry number 7554-65-6 DESCRIPTION Fomepizole Injection is a competitive inhibitor of alcohol dehydrogenase. The chemical name of fomepizole is 4-methylpyrazole. It has the molecular formula C4H6N2 and a molecular weight of 82.1 g/mol. It is a clear to yellow liquid at room temperature. Its melting point is 25oC and it may present as a solid at room temperature. Fomepizole is soluble in water in water and very soluble in ethanol, diethyl ether, and chloroform. Each vial contains 1.5 mL (1 g/mL) of fomepizole. It is supplied sterile. Fomepizole injection does not contain any excipients. PHARMACOLOGY Mechanism of Action: fomepizole is a competitive inhibitor of alcohol dehydrogenase. Alcohol dehydrogenase catalyses the oxidation of ethanol to acetaldehyde. Alcohol dehydrogenase also catalyses the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites. Ethylene glycol, the main component of most antifreezes and coolants, is metabolized to glycoaldehyde, and oxalate. Glycolate and oxalate are the metabolic by-products primarily responsible for the metabolic acidosis and renal damage seen ethylene glycol toxicosis. The lethal dose of ethylene glycol in humans is approximately 1.4 mL/kg. Methanol, the main component of windshield wiper fluid, is slowly metabolized via alcohol dehydrogenase to yield formic acid. Formic acid is primarily responsible for the metabolic acidosis and visual disturbances (e.g. decreased visual activity and potential blindness) associated with methanol poisoning. A lethal dose of methanol in humans is approximately 1- 2 mL/kg. Fomepizole has been shown in vitro to block alcohol dehydrogenase enzyme activity in dog, monkey and human liver. The concentration of fomepizole at which alcohol dehydrogenase is inhibited by 50% in vitro is approximately 0.1 µmol/L. In animal studies, fomepizole has been shown to inhibit the formation of toxic metabolites of ethylene glycol and methanol, to reverse acidosis and to prevent mortality and ethylene-glycol induced renal damage. Fomepizole in the range of 100 to 300 µmol/L (8.6 – 24.6 mg/L) has been targeted to assure adequate plasma concentrations in humans for the effective inhibition of alcohol dehydrogenase. 1 FOMEPIZ-AU-PI-v11 AusPAR Antizol Fomepizole AFT Pharmaceuticals PM-2015-02803-1-3 Final 17 August 2017 In healthy volunteers, oral doses of fomepizole (10 – 20 mg/kg) significantly reduced the rate of elimination of moderate doses of ethanol, which is also metabolized through the action of alcohol dehydrogenase (see PRECAUTIONS, Interactions with other Medicines). Pharmacokinetics: The plasma half-life of fomepizole varies with dose, even in patients with normal renal function (GFR ≥90mL/min/1.73m2), and has not been calculated. Distribution: After intravenous infusion, fomepizole rapidly distributes to total body water. The volume of distribution is between 0.6 L/kg and 1.02 L/kg. Metabolism: In healthy volunteers, only 1 – 3.5% of the administered dose of fomepizole (7- 20 mg/kg oral and IV) was excreted unchanged in the urine, indicating that metabolism is the major route of elimination. In humans, the primary metabolite of fomepizole is 4-carboxypyrazole (approximately 80 – 85% of administered dose), which is excreted in the urine. Other metabolites of fomepizole observed in the urine are 4-hydroxymethylpyrazole and the N-glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole. With multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed- function oxidase system, which produces a significant increase in the elimination rate after about 30 – 40 hours. After enzyme induction, elimination follows first-order kinetics. Excretion: The elimination of fomepizole is best characterized by Michaelis-Menten kinetics after acute doses, with saturable elimination occurring at therapeutic blood concentrations [100 – 300 µmol/L, 8.2 – 24.6 mg/L]. Fomepizole and its metabolites are renally excreted. With multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed- function oxidase system, which produces a significant increase in the elimination rate after about 30 – 40 hours. After enzyme induction, elimination follows first-order kinetics. Clinical Trials The efficacy of fomepizole in the treatment of ethylene glycol and methanol intoxication was studied in two prospective, U.S. clinical trials without concomitant control groups. The clinical trials described below were supplemented by open-label studies and case reports from the published literature. An open-label, multi-dose, multi-centre, phase III pivotal trial for treatment of ethylene glycol poisoning with fomepizole has been conducted. Eligible subjects were male or female over 12 years of age who presented with a documented serum ethylene glycol concentration of >20 mg/dL (3.2 mmol/L); OR a history (or strong clinical suspicion) of ethylene glycol ingestion along with arterial pH<7.3, serum bicarbonate <20 mEq/L, osmolar gap by freezing point depression >10 mOsm/L, and/or oxalate crystals in urine; OR recent (<1 hour) documented history of a potentially toxic amount of ethylene glycol and osmolar gap >10 mOsm/L. All patients received fomepizole shortly after admission with a loading dose of 15 mg/kg body weight fomepizole followed by supplemental doses of 10 mg/kg over 30 minutes at intervals of 12 hours (or 15 mg/kg after 48 hours to compensate for increased elimination after 30 – 40 hours after multiple doses) until the serum ethylene glycol level was reduced to ≤ 20 mg/dL (3.2 mmol/L). Fourteen of 16 patients being treated with fomepizole for ethylene glycol poisoning underwent haemodialysis because of severe intoxication (see DOSAGE AND ADMINISTRATION). There were no differences in outcomes between those who did and did not undergo haemodialysis. Fomepizole levels fell faster during haemodialysis than when due to endogenous clearance alone. During haemodialysis, fomepizole levels fell at a median rate of 0.8 µmol/L/minute (range 0.27 to 4.4). In the absence of haemodialysis, levels fell at a median rate of 0.33 µmol/L/minute (range 0.1 to 0.83). Median clearance of fomepizole by dialysis was 183 mL/min (range 129 – 218 mL/min). 2 FOMEPIZ-AU-PI-v11 AusPAR Antizol Fomepizole AFT Pharmaceuticals PM-2015-02803-1-3 Final 17 August 2017 The results of the ethylene glycol study provide evidence that fomepizole blocks ethylene glycol metabolism mediated by alcohol dehydrogenase in the clinical setting. Plasma concentrations of toxic metabolites of ethylene glycol failed to rise in the initial phases of treatment. The relationship to fomepizole therapy, however, was confounded by haemodialysis and significant blood ethanol concentrations in many of the patients. Nevertheless, in the post-dialysis period(s), when ethanol concentrations were insignificant and the concentrations of ethylene glycol >20 mg/dL (>3.2 mmol/L), the administration of fomepizole alone blocked any rise in glycolate concentrations. An open-label, multi-dose, multi-centre, phase III pivotal trial for treatment of methanol poisoning has been conducted. Eligible subjects were male or female patients over 12 years of age who presented with a documented serum methanol level of >20 mg/dL (> 6.24 mmol/L) OR a history (or strong clinical suspicion) of methanol intoxication and presented with at least two of the four following criteria: arterial pH<7.3, serum bicarbonate <20 mEq/L, osmolar gap by freezing point depression >10 mOsm/L, and/or recent (less than 1 hour) documented history of an ingestion of a potentially toxic amount of methanol). All patients received fomepizole shortly after admission with a loading dose of 15 mg/kg body weight fomepizole followed by supplemental doses of 10 mg/kg at intervals of 12 hours(or 15 mg/kg after 48 hours) until the serum ethylene glycol level was reduced to ≤ 20 mg/dL (6.24 mmol/L) . Seven of 11 patients in the trial for treatment of methanol poisoning underwent haemodialysis because of severe intoxication (see DOSAGE AND ADMINISTRATION). There was no difference in outcome for these patients compared to the non-dialysis patients. The results of the methanol study provide evidence that fomepizole blocks methanol metabolism mediated by alcohol dehydrogenase in the clinical setting. Plasma concentrations of toxic metabolites of methanol failed to rise in the initial phases of treatment. The relationship to fomepizole therapy, however, was confounded by haemodialysis and significant blood ethanol concentrations in many of the patients. Nevertheless, in the post-dialysis period(s), when ethanol concentrations were insignificant and the concentrations of methanol were >20 mg/dL (6.24 mmol/L), the administration of fomepizole alone blocked any rise in formate concentrations. INDICATIONS Antizol® (fomepizole) is indicated for the treatment of ethylene glycol or methanol poisoning. (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Fomepizole should not be administered to patients with a documented serious hypersensitivity reaction to fomepizole or other pyrazoles. Fomepizole should not be used in patients with ethanol intoxication. Fomepizole should not be used in patients exposed to poisons other than ethylene glycol or methanol alone or in combination (including diethylene glycol). PRECAUTIONS